Catalase activity and arsenic sensitivity in acute leukemia.
Arsenic trioxide (As2O3) is currently employed as a treatment for relapsed acute promyelocytic leukemia (APL), where it can induce remission in greater than 90% of patients, but is ineffective in patients with non-APL acute myeloid leukemia (AML). As2O3 induces apoptosis in APL cells through mechanisms dependent and independent of the PML-RARalpha fusion protein. Through PML-RARalpha fusion-independent mechanisms, As2O3 increases H2O2 production via its effects on glutathione and glutathione peroxidase. Catalase is an alternative mechanism to convert H2O2 to water. Therefore, we explored the relationship between catalase activity and As2O3 sensitivity. In AML and APL cell lines, but not primary patient samples, basal catalase levels matched sensitivity to As2O3. However, the chemical inhibition of catalase did not enhance As2O3-induced cell death. Failure of catalase inhibition to sensitise cells to As2O3 was due to a failure of catalase inhibition to increased levels of reactive oxygen species. Therefore, other strategies should be explored to enhance the cytotoxicity of As2O3 in AML.
Coe
Emma
E
Ontario Cancer Institute, Princess Margaret Hospital, and Department of Medical Biophysics, University of Toronto, Toronto, Canada.
Schimmer
Aaron D
AD
D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D002374:Catalase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy*; D010087:Oxides / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D001152:Arsenicals; D004791:Enzyme Inhibitors; D010087:Oxides; D002374:Catalase; D000077237:Arsenic Trioxide